固相片段法合成利拉鲁肽

Study on the solid-phase synthetic process of liraglutide

目的 研究利拉鲁肽的固相合成。方法 通过汇聚式合成策略,利用固相片段缩合法制备利拉鲁肽。以芴甲氧羰基(Fmoc)保护的氨基酸为原料,分别合成4个全保护多肽片段,依照肽序依次偶联得到全保护利拉鲁肽主链[GLP-1(7-37)],经缩合反应在第20位赖氨酸引入侧链Nα-棕榈酰基-L-谷氨酰基,最后将其从树脂上切割并脱保护得到利拉鲁肽。结果与结论利拉鲁肽粗肽收率为25.65%,纯度为52.35%。采用制备型反相高效液相色谱技术进行分离纯化后,利拉鲁肽纯度为98.42%。该合成工艺反应条件温和、操作简单、合成周期短,是实验室规模下较好的利拉鲁肽制备方法。

Liraglutide is a human glucagon-like peptide-1(GLP-1) receptor agonist developed by Novo Nordisk.In this study, the total synthesis of the antidiabetic peptide liraglutide was described.Liraglutide was synthesized via a convergent approach from four peptide fragments prepared by Fmoc-strategy solid phase peptide synthesis(SPPS).The synthetic process has many advantages such as mild reaction condition, synthetic feasibility as well as acceptable yield.This study provides a practical preparative process of liraglutide on lab scale.